N,n{40 -bis-(ethylene)-4,4{40 -bipiperidyl dichloride growth promoting compound and method of using same

ABSTRACT

The compound of this invention is especially useful for promoting the growth of vertebrate animals.   The novel compound N,N&#39;&#39;-bis-(ethylene)-4,4&#39;&#39;-bipiperidyl dichloride is provided which is represented by the formula

United States Patent 1191 Rutman 11 3,723,62 1 1451 Mar. 27, 1973 [75] Inventor: Robert J, Rutman, Philadelphia, Pa.

[73] Assignee: The Trustees of the University of Pennsylvania, Philadelphia, Pa.

[22] Filed: Mar. 2, 1970 [21 Appl. No.: 20,264

Related US. Application Data [60] Division of Ser. No. 838,641, July 2, 1969, Pat. No. 3,575,987, which is a continuation-in-part of Ser. No. 540,498, April 6, 1966, abandoned.

52 US. C1 ..424/267, 99/2 G 51 Int. (:1. ..A61k 27/00 58 Field of Search ..424/267; 260/293; 99/2 G [56] References Cited UNITED STATES PATENTS 2,624,734 I 1/1953 Goldberg ..260/293 3,575,987 4/1971 Rutman ..424/267 Primary ExaminerJerome D. Goldberg Assistant Examiner-Vincent D. Turner Att0rneyPaul & Paul ABSTRACT The novel compound N,N'-bis-(ethylene )-4,4- bipiperidyl dichloride is provided which is represented by the formula The compound of this invention is especially useful for promoting the growth of vertebrate animals.

5 Claims, N0 Drawings N ,N '-BIS-(ETHYLENE)-4,4'-BIPIPERIDYL DICHLORIDE GROWTH PROMOTING COMPOUND AND METHOD OF USING SAME CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application, filed under the provisions of Rule 147, of my application, Ser. No. 838,641, filed July 2, 1969, now US. Pat. No. 3,575,987 which in turn is a continuation in part of application, Ser. No. 540,498 filed Apr. 6, 1966, now abandoned.

BACKGROUND OF THE INVENTION l. Field of the Invention This invention relates to a compound and method for increasing the growth rate and weight gain of animals. More particularly, this invention is directed to a compound and method for modifying the appetite regulatory system of warm-blooded vertebrate animals in such a way as to induce food intake in excess of caloric requirements, and thereby producing significant and lasting weight gains.

2. Description of the Prior Art.

At the present time, the principal and most important commercial growth promoter for animals is diethylstilbestrol which is an estrogenic substance having the well known inherent undesirable side effects of this class of compounds. Considerable research has been directed towards finding non-estrogenic growthpromoting compositions. This has resulted in the discovery of various antibiotic growth stimulants which, in turn, also presents problems when used commercially.

It is, accordingly, an object of this invention to provide a growth-promoting compound which is non-estrogenic and non-antibiotic.

A further object of this invention is to provide a method for increasing weight and growth rate in animals, particularly in rodents and livestock.

An additional object of this invention is to provide a growth-promoting compound which produces significant weight gains in vertebrate animals following a single administration of the compound in a sufficient amount relative to the body weight of the animal.

SUMMARY OF THE INVENTION [V \N/ L The compound of this invention may be considered to be the cyclic immonium ion form of N,N-bis-(B- chloroethyl)-4,4'-bipiperidine.

A single administration of a composition containing the compound of formula I in a physiologically active amount, for example 5 milligrams to milligrams of the compound per kilogram of the animal weight is sufficient to produce the desired growth-promoting results.

DESCRIPTION OF THE PREFERRED EMBODIMENT The precurser for the compound of the present invention is N,N'-bis-(B-chloroethyl)-4,4'-bipiperidine which is represented by the formula ClCHzCH2N NCH2CH2CI When N,N-bis-(B-chloroethyl)-4,4'-bipiperidine was evaluated in screening tests, it was found to be substantially physiologically inert. More particularly, when N,N'-bis-(B-bipiperidine was tested for its effect on the growth rate of animals, it was found to have no growth-promoting or fattening effect on the animals.

It was found, however, that when N,N'-bis-(B- chloroethyl)-4,4-bipiperidine was converted into the cyclic immonium ion form represented by the formula The cyclic immonium ion compound of this invention is obtained by reacting N,N-bis-(B-chloroethyl)- 4,4'-bipiperidine in an aqueous alkaline reaction medium having a pH from about 7.5 to about ll and preferably about 9. The pH is advantageously controlled at a preselected pH with a suitable buffer system, for example Na B O and NaOH, NH Cl and NH or Na HPQ, and NaOH. When using a borate type buffer, a O. lN solution has been found to give optimum results when conducting the cyclicization at pH 9. The reaction is preferably conducted at ambient to slightly elevated temperatures, for example from about 22 to about 45C with the optimum temperature being about 37C. The length of time required to complete the cyclicization of the N,N'-bis-(B-chloroethyl)-4,4- bipiperidine depends to a large extent on the pH. At the lower pH range, the time is considerably longer with reaction times up to two hours being required while at the higher pH range, for example pH ll as little as fifteen minutes is generally sufficient to complete the reaction. At the preferred pH of about 9, about 45 to minures of reaction time are required.

The reaction product which contains the active compound of this invention may be used directly if a physiologically inert reaction medium is employed for the cyclicization. However, it is also possible to isolate the active compound of this invention from the reaction medium and then add the component to a physiologically inert carrier such as distilled water or saline. The compounds of this invention may also be mixed with other active compounds such as vitamins and the like and the combination added in a single dose to the animal to be treated.

The composition containing the cyclic immonium compounds of this invention may be administered orally, either directly or by adding it to the water or feed stuff of the animal to be treated. it has been found, however, that the most effective way of administering the compositions of this invention is by intra-peritoneal injection.

The growth-promoting cyclic immonium compounds of this invention is administered to animals in a physiologically active amount. An amount of about five milligrams to about 25 milligrams per kilogram of animal weight is sufficient to provide a significant growth-promoting effect. The amount required to produce the growth-promoting result is generally administered in a single dose. The treated animal is then provided with a quantity of feed in excess of its normal caloric requirement. Since the compounds of the present invention apparently produce a lasting change in the appetite regulatory system of the animal to which it is administered in the direction of enhanced appetite beyond caloric requirement, there is a gain in weight which is very noticeable over a period of time in the order of3 to 16 weeks.

The growth-promoting method of this invention is applicable to a large number of animals including rodents, such as mice, rats and squirrels, and to other vertebrate animals, such as poultry, ruminants and swine. In the case of fattening livestock for the market, the commercial utility of the present invention is apparent. In the case of the rodents, there is a further utility, namely, the provision of a means for studying in animals the mechanisms involved in growth and fattening and in appetite regulatory systems.

In the following example, the amounts referred to are by weight.

EXAMPLE 1 Hybrid mice (C3D2) were treated by intraperitoneal injection [ip] of aqueous composition containing 25 milligrams of the compound of this invention per kilogram of treated animal. Standardized mouse feed was provided in amounts substantially exceeding the normal daily feed amounts consumed by mice of this strain. Untreated litter mates were provided the same amounts of the same standardized feed under identical conditions..-The treated mice consumed 5.0 to 5.5 grams of feed per day compared with 1.5 to 1.7 grams per day for the littermate controls. Both the treated animals and the controls were sleek, alert, agile and active, and appeared to be normal in every way except for a marked increase in appetite in the treated mice and a substantial increase in weight and size in the treated mice. The comparative weight gains between treated and untreated mice were as follows:

Weight of Weight of Time Treated Untreated (Weeks) Mice Mice O 20 grams 20 grams 2 23 g I 20 g 3 26 grams 20 grams 4 31 g 2l g 5 35 g 22 g 6 37 g 23 g 7 42 g 23 g 8 44 g 24 g 9 47 g 24 g l0 50 g 25 g l l 53 g 25 g Administration of smaller amounts of the compound of this invention produces weight gains which are comparable but somewhat smaller in magnitude than the weight gains included in the above tables. The preferred range particularly for the fattening of larger animals, such as poultry, lambs, swine and cattle, is from 5 milligrams to 15 milligrams of the composition of this invention per kilogram of animal weight. Since in all cases the weight gain is the result of converting food to fatty materials in the animal, it is necessary to make available to the animal a sufficient quantity of feed to satisfy, at least in part, the enhanced animal appetite.

I claim:

1. A method of fattening a warm blooded animal which comprises orally or intraperitoneally administering an appetite enhansing effective amount of the compound of the formula to said animal.

2. The method of claim 1 wherein said effective amount is from about 5 to 25 milligrams per kilogram of animal weight. w

3. The method of claim 1 wherein the administration is carried out by intraperitoneal injection.

4. The method of claim 1 wherein said effective amount is administered in a single dose.

5. A composition of matter comprising-an appetite enhansing effective amount of compound of the formua W W and a physiologically inert carrier. 

2. The method of claim 1 wherein said effective amount is from about 5 to 25 milligrams per kilogram of animal weight.
 3. The method of claim 1 wherein the administration is carried out by intraperitoneal injection.
 4. The method of claim 1 wherein said effective amount is administered in a single dose.
 5. A composition of matter comprising an appetite enhansing effective amount of compound of the formula 